Doctor of Philosophy

dissertationAbstraction plays an important role in digital design, analysis, and verification, as it allows for the refinement of functions through different levels of conceptualization. This dissertation introduces a new method to compute a symbolic, canonical, word-level abstraction of the function implemented by a combinational logic circuit. This abstraction provides a representation of the function as a polynomial Z = F(A) over the Galois field F2k , expressed over the k-bit input to the circuit, A. This representation is easily utilized for formal verification (equivalence checking) of combinational circuits. The approach to abstraction is based upon concepts from commutative algebra and algebraic geometry, notably the Grobner basis theory. It is shown that the polynomial F(A) can be derived by computing a Grobner basis of the polynomials corresponding to the circuit, using a specific elimination term order based on the circuits topology. However, computing Grobner bases using elimination term orders is infeasible for large circuits. To overcome these limitations, this work introduces an efficient symbolic computation to derive the word-level polynomial. The presented algorithms exploit i) the structure of the circuit, ii) the properties of Grobner bases, iii) characteristics of Galois fields F2k , and iv) modern algorithms from symbolic computation. A custom abstraction tool is designed to efficiently implement the abstraction procedure. While the concept is applicable to any arbitrary combinational logic circuit, it is particularly powerful in verification and equivalence checking of hierarchical, custom designed and structurally dissimilar Galois field arithmetic circuits. In most applications, the field size and the datapath size k in the circuits is very large, up to 1024 bits. The proposed abstraction procedure can exploit the hierarchy of the given Galois field arithmetic circuits. Our experiments show that, using this approach, our tool can abstract and verify Galois field arithmetic circuits up to 1024 bits in size. Contemporary techniques fail to verify these types of circuits beyond 163 bits and cannot abstract a canonical representation beyond 32 bits

CONSIDERING THE EXPERIMENTAL USE OF TEMOZOLOMIDE IN GLIOBLASTOMA RESEARCH

Temozolomide (TMZ) currently remains the only chemotherapeutic component in the approved treatment scheme for Glioblastoma (GB), the most common primary brain tumour with a dismal patient’s survival prognosis of only ~15 months. While frequently described as an alkylating agent that causes DNA damage and thus—ultimately—cell death, a recent debate has been initiated to re-evaluate the therapeutic role of TMZ in GB. Here, we discuss the experimental use of TMZ and highlight how it differs from its clinical role. Four areas could be identified in which the experimental data is particularly limited in its translational potential: 1. transferring clinical dosing and scheduling to an experimental system and vice versa; 2. the different use of (non-inert) solvent in clinic and laboratory; 3. the limitations of established GB cell lines which only poorly mimic GB tumours; and 4. the limitations of animal models lacking an immune response. Discussing these limitations in a broader biomedical context, we offer suggestions as to how to improve transferability of data. Finally, we highlight an underexplored function of TMZ in modulating the immune system, as an example of where the aforementioned limitations impede the progression of our knowledge

A high quality draft consensus sequence of the genome of a heterozygous grapevine variety

Worldwide, grapes and their derived products have a large market. The cultivated grape species Vitis vinifera has potential to become a model for fruit trees genetics. Like many plant species, it is highly heterozygous, which is an additional challenge to modern whole genome shotgun sequencing. In this paper a high quality draft genome sequence of a cultivated clone of V. vinifera Pinot Noir is presented. We estimate the genome size of V. vinifera to be 504.6 Mb. Genomic sequences corresponding to 477.1 Mb were assembled in 2,093 metacontigs and 435.1 Mb were anchored to the 19 linkage groups (LGs). The number of predicted genes is 29,585, of which 96.1% were assigned to LGs. This assembly of the grape genome provides candidate genes implicated in traits relevant to grapevine cultivation, such as those influencing wine quality, via secondary metabolites, and those connected with the extreme susceptibility of grape to pathogens. Single nucleotide polymorphism (SNP) distribution was consistent with a diffuse haplotype structure across the genome. Of around 2,000,000 SNPs, 1,751,176 were mapped to chromosomes and one or more of them were identified in 86.7% of anchored genes. The relative age of grape duplicated genes was estimated and this made possible to reveal a relatively recent Vitis-specific large scale duplication event concerning at least 10 chromosomes (duplication not reported before). Sanger shotgun sequencing and highly efficient sequencing by synthesis (SBS), together with dedicated assembly programs, resolved a complex heterozygous genome. A consensus sequence of the genome and a set of mapped marker loci were generated. Homologous chromosomes of Pinot Noir differ by 11.2% of their DNA (hemizygous DNA plus chromosomal gaps). SNP markers are offered as a tool with the potential of introducing a new era in the molecular breeding of grape